The present invention relates to techniques for determining or predicting the secondary structure of a polypeptide, a protein, or an autonomous folding region thereof.
The secondary and higher-order structures of a protein dictate its function and biological activity, and are therefore critical to many fundamental life processes. Experimentally, such structures are often obtained through crystallography based on the assumption that the most stable conformation of a protein in solution is approximately the same as when it is crystallized. However, crystallography of a majority of proteins is currently unfeasible, presumably because chain flexibility and complex interactions existent within a protein molecule prevent it from forming crystals from solution.
Computational methods provide an alternative tool to explore protein structure, and are particularly valuable when a protein structures are inaccessible by crystallography or other experimental techniques. One computational approach to the determination of protein structure is based on energy minimization. The energy minimization approach, however, requires that the global (or molecular) free energy change to be mathematically describable in terms of local atomic bonding energies, and therefore cannot always provide an accurate description of the most stable protein secondary structure at the free energy minimum.
Furthermore, energy minimization methods do not address response speed and axis of rotation limitations, and as a result the models generate unrealistically-quick onsets of protein folding and/or volume change. Another approach, of which Molecular Dynamics is a typical example, employs explicit Newtonian motion functions to provide a time trajectory of a molecular system evolution. See Berendsen, H. J. C., Postma, J. P. M., van Gunsteren, W. F., DiNola, A., and Haak, J. R., J. Chem. Phys. 81, 8, 3684, (1984), and Karplus, Martin and McCammon, J. Andrew, Nat. Struc. Biol. 9, 9, 646 (2002).
This approach is severely limited by the small time steps needed to make it physically meaningful, as well as by the complex mathematical integration schemes needed to compute the motion functions. Therefore, it is best suited for exploration of molecular phenomena occurring over a short timeframe or for small size molecules, but is of little use for molecular phenomena occurring over a longer timeframe, such as protein folding. See Mirny, Leonid and Shakhnivich, Eugene, Annu. Rev. Biomol. Sturuct. 30, 361-96 (2001)).
Accordingly, there exists a need for a simulation method that incorporates the random forces imposed by the surrounding media and the relationship of their temporal dimension to the internal forces of a protein molecule, which method can significantly reduce the time required for a protein folding simulation, so that it becomes feasible for regular desktop computers to handle such a task.